Original studies demonstrated virus-specific and species-specific differences in the susceptibilities of simian virus 40 (SV40)-\and adenovirus (Ad) 2-transformed (tf) cells to the lytic effects of activated macrophages (AM). SV40-tf hamster cells were resistant to lysis, whereas SV40-tf mouse and rat cells and Ad2-tf hamster cells were susceptible to lysis by the same AM populations. In vivo data suggested a correlation between the nonlytic phenotype and tf cell resistance to allograft rejection. Clonally derived inbred LSH hamster cell lines tf by Ad2, Ad12 or SV40 have been compared for tumor-inducing capacity in various hosts and for susceptibility to AM and to spontaneous spleen cell-mediated cytolytic (SCMC) activity. The tumor-inducing capacities of Ad2-, Ad12-, and SV40-tf hamster cells define four distinct tumorigenic phenotypes: type I, nononcogenic for newborn hamsters but oncogenic for nude mice (two Ad2-tf lines); type II, oncogenic for newborn hamsters but nononcogenic for syngeneic adults (13 Ad2-tf lines); type III, oncogenic for both newborns and syngeneic adults (Ad12-tf lines); and type IV, almost equally oncogenic for syngeneic and allogeneic adult hamsters (SV40-tf lines). Ad12-tf (type III) and SV40-tf (type IV) cell lines were relatively resistant to SCMC activity compared with Ad2-tf (types I and II) cell lines. Only SV40-tf (type IV) cell lines were resistant to lysis by BCG-AM. These differential patterns of susceptibility to cytolysis suggest an association between the level of DNA virus tf hamster cell resistance to lysis by nonspecific host effector cells and the oncogenicity of the transforming virus. To evaluate the role of virus-encoded cellular proteins in the tf cell's cytolytic susceptibility, somatic cell hybrids were formed between an Ad2 (type II, susceptible to lysis)-\and an SV40 (type IV, resistant to lysis)-tf hamster cell line. Using assays of BCG-AM and SCMC activity, it was observed that cell hybrids that expressed Ad2 nonvirion tumor (T) antigens exhibited increased cytolytic susceptibility compared with Ad2 T antigen negative cell hybrids or nonhybrid SV40-tf cells. No correlation was found between the expression of SV40 T antigen in hybrid cells and cytolytic susceptibility. These results suggest the existence of a novel function of early Ad2 genome-encoded polypeptides in transformed cells--the induction of susceptibility to destruction by immunologically nonspecific effector cells.